Derivatives of 2,1-benzisothiazoline

ABSTRACT

The compounds are 2,1-benzisothiazolines substituted in the 3position which are useful pharmaceutical agents, especially central nervous system stimulants and antihypertensive agents. Compounds disclosed include 1,3-dimethyl-3-(3&#39;&#39; -hydroxypropyl)2,1-benzisothiazoline-2,2-dioxide, 1,3-dimethyl-3-(N-carbethoxy2&#39;&#39; -aminoethyl)-2,1-benzisothiazoline-2,2-dioxide, and 1,3dimethyl-3-(3&#39;&#39;-dimethyl--guanidinopropyl)-2,1-benzisothiazoline2,2 -dioxide.

United States Patent 91 Skorcz et a1.

[54] DERIVATIVES OF 2,1-

BENZISOTHIAZOLINE [75] Inventors: Joseph A. Skorcz, Mi lwaukee; John T. Suh; Claude I. Judd, both of Mequon, all of Wis.

[73] Assignee: Colgate-Palmolive Company, New

York,N.Y.

[22] Filed: Nov. 3, 1971 [21] -Appl. No; 195,481

Related U.S. Application Data [63] Continuation-impart of Ser. No. 32,461, April 27,

1970, Pat. No. 3,657,238, and a continuation-in-part of Ser. No. 682,974, Nov. 14, 1967, Pat. No.

3,528,989, and a continuation-in-part of Ser. No. 571,967, Aug. 12, 1966, abandoned.

9/1970 Skorcz et a1 ..260/304 1 Apr. 3, 1973 9/1970 Skorcz et al ..260/304 3,560,512 2/1971 Skorcz et al... .....260/301 3,657,238 4/1972 Skorcz et al..'. ..260/301 Primary ExaminerAlex Maze] Assistant Examiner-R. J. Galllagher Attorney-T. F. Kryshak et al.

57 ABSTRACT A The compounds are 2,1-benzisothiazolines substituted in the 3-position which are useful pharmaceutical agents, especially central nervous system stimulants and antihypertensive agents. Compounds disclosed include 1,3-dimethy1-3-(3 '-hydroxypropyl)-2, l

benzisothiazoline-Z,2-dioxide, 1,3-dimethyl-3-(N-carbethoxy-2'-aminoethyl)-2,1-benzisothiazo1ine-2,2- dioxide, and 1,3-dimethy1-3-(3 -dimethyl-- guanidinopropyU-Z,1-benzisothiazoline-2.2-dioxide.

7 Claims, N0 Drawings DERIVATIVES OF 2,l -BENZISOTHIAZOLINE 'RELATED'CASES The present application is a continuation-in-part of our earlier applications Ser. No. 032,461 filed Apr. 27,

197-0 now US. Pat. No. 3,657,238; Ser. No. 682,974,

filed Nov. 14, l967,-now U.S.Pat. No. 3,528,989; and Ser. No. 571,967 filed Aug. 12,1966, now abandoned.

QDETAILEDIDESCRIPTION The novel compounds, of the present invention may be represented bythe following formula R1 B-Am in which X and Y are selected from hydrogen, lower alkyl of one to four carbon atoms such as methyl, ethyl or propyl, lower alkoxy such as methoxy, ethoxy and propoxy, aralkoxy such as benzyloxy, nitro, halogen such as bromo or chloro and trifluoromethyl; R is selected from a, lower alkyl of one '-to four carbon atoms, a cycloa'lkyl of three to seven carbon=atoms such as cyclopropyl, cyclohexyl orcyclopentyl,acycloalkyllower alkyl in which the cycloal'kyl contains three to (dimethyla minop'ropyl)-2-piperidyl, 'N-phcnyl-lower alkyl-3 or 4-piperidyls such as N-benz-yl-3-piperidyl, N-

seven carbon atoms such as cyclopropylmeth-yl,

cyclopentylmethyl and cyclohe xylethyl, phenyl, a nuclearsubstituted -phe nyl,particularly a lower alk-oxysubstituted'phenyl such asp-methoxyphenyl,oran aralkyl of seven to l 1 carbon atoms, particularly aap'henyllower alkyl such as benzyl, :phenylisopropyl, R 'is R,

phenylethyl-4-piperidyl and N-phenylpropyl-3- piperidyl, Z-piperidyl, 3-piperidyl and 4-piperidyl, 2- pyr'rolidyl, 3pyrrolidyl, N-lower alkyl-2 or 3-pyrrolidyls such as'N methyl-2-pyrrolidyl, N-ethyl-3-pyrrolidyl, N- propyl-4-pyrrolidyl, N-phenyl-lower alkyl-2 or 3-pyrrolidyls such as N-benzyl-2-pyrrolidyl 'and'N-phen- -ylethyl-3-pyrrolidyl and 3-quinuclidyl; provided, however, that B can be a single chemical bond when Am is a cyclic aminegroup.

The compounds of the invention in which Am is -*and R andR are not hydrogen, may be conveniently prepared by employing a haloaniline such as o- .chloroaniline or m'-bromoaniline, or an N-substituted haloaniline such as N-phenyl-o-chloroaniline, .or N-p- 'methoxyphenyl-o-bromoaniline as the basic starting material. I If an unsubstituted haloaniline is employed, itis first treated with methanesulfonyl chloride to form a h-alomethane-sulfonanilide; the sulfoanilide is then t'reatedwith-an alkyl ester such as dimethyls'ulfate, and -abase suchas'potassiumhydroxide, to;form an N-substituted h'alomethanesulfonanilide. The thus obtained 'sulfonanilideis then treated with anon-participating s 'trongbase, for example analkali amide such as sodium'am'ide in'an inert reaction medium such as liquid hydrogen or benzyl; B is a single chemical bond or *a straight-or branched'chain alkyleneof two to six'carb'on atoms, and Am is'hydroxy,

NH /'R1 -NH-&-NH, -N

in which R is selected from a-loweracyl of one to four carbon atoms such as acetyl or p'ropionyl or a-lower carboalkoxy such as carbomethoxy orcarbethoxy, R is hydrogen or R and in which R and R are joined together to form amino groups in whichthe'nitrogen is part of the cyclic group such as a morpholino,pyrrolidino, .pi'peridino, 1,23,4-

tetrahydroisoquinolino, l,2,3,4 tetrahydroquinolino, a

diethylaminoethyl)-3-piperidyl and N- ammonia,anhydrous ether, benzene or the like, to effect' ring closure. The l-substituted-2,lbenzisothiazoline-2,2-dioxide thus obtained can then be treated withan appropriate ester in the presence of abaseto form the desired amine.

The described process may be diagrammed as follows:

base I inert reaction medium Ri B-Am X l X aminoallryl (star whereinR,"R,, X and Y are groups which-do not interfere withor partake in the reaction.

If an N-substitut'ed haloaniline is employed as the starting material, it is first treated with m'ethanesulfonyl chloride to form the methanesulfonanilide derivative which may be treated directly with a suitable base in an inert reaction medium to effect ring closure. The 1,3- disubstituted-2, l -benzisothiazoline-2,2-dioxide thus obtained is then treated with an appropriate ester in the presence of base to form the desired compound.

This process may be diagrammed as follows:

wherein R, R X and Y are groups which do not interfere with or partake in the reaction.

Among the aminoalkyl esters which can be employed in the above processes are the following:

3-diemthylaminopropyl chloride,

3-diphenylaminopropyl chloride, 2-dibenzylaminoethyl chloride, 2-dicyclohexylaminoethyl bromide, 3-piperidinopropyl chloride,

morpholinoethyl chloride,

pyrrolidinoethyl chloride,

4-methylpiperazinoethyl chloride,

3-(N-methyl-N-benzylamino)propyl chloride,

2-dimethylaminoethyl tosylate, 2-(N-methyl-N-benzylamino)ethyl chloride, and 2-diethylaminoethyl bromide.

Representative of the novel compounds which can be prepared by employing the aminoalkyl esters in the described process are the following:

l-methyl-3-dimethylaminoethyl-2, l

benzisothiazoline-Z,2-dioxide, 1-phenethyl-3-dimethylaminoethyl-2, l

benzisothiazoline-2,2-dioiride, l-methyl-3-benzylmethylaminoethyl-Z, l

benzisothiazoline-2,2-dioxide, l-methyl-3-phenyl-3-( 2 -benzylmethylaminoethyl 2, l -benzisothiazoline-2,2-dioxide, 1-phenethyl-3-(2 '-benzylmethylaminoethyl )-2, l

benzisothiazoline-2,2-dioxide,

1-phenyl-3-( 2 '-benzylmethylaminoethyl )-2, 1

benzisothiazoline-2,2-dioxide, l,3-dimethyl-3-(2'-benzylmethylaminoethyl)-2,l

benzisothiazoline-2,2-dioxide. 1-methyl-3-(2'-piperidinoethyl)-2, l

' benzisothiazoline-2,2-dioxide,

l-ethyl-3-( 3 '-N-methylpiperazinopropyl)-2,1

benzisothiazoline-2,2-dioxide,

l-propyl-3-( 2'-morpholinoethyl )-2, 1

benzisothiazoline-2,2-dioxide, l-ethyl-3-methyl3-(3'-dimethylaminopropyl)-2,l-

benzisothiazoline-2,2-dioxide,

l-phenethy1-3-( 2'-N-methylpiperazinoethyl )-2, l

benzisothiazoline-Z,2-dioxide, l-cyclopentylmethyl-3-(3'-morpholinopropyl)-2,l-

benzisothiazoline-2,2-dioxide,

l-ethyl-3-phenyl-3-(4-N-methylpiperazinopropyl)- 2, l -benzisothiazoline-2,2-dioxide,

l-ethyl-3-phenyl-3-(2'-piperidinoethyl)-2,l-

benzisothiazoline-2,2-dioxide,

The compounds in which Am is benzyl and R is not hydrogen or benzyl to catalytic 1 cleavage of the benzyl group.

Similarly, the compounds in which Am is and both R and R are hydrogen may be prepared by subjecting the corresponding compound in which R and R are benzyl to catalytic cleavage of the benzyl groups. 7

The catalytic cleavage of the benzyl group may be readily effected by dissolving the N-mono or dibenzyl derivative in a suitable medium and adding a catalyst, such as palladium on carbon, and hydrogen under pressure, as up to about psi. The cleavage may also be effected by reacting the appropriate benzyl derivative with a chloroformate such as methyl chloroformate, ethyl chloroformate or the like, to form the corresponding N-carboalkoxy derivative, and subjecting that compound to hydrolysis conditions.

Representative of the compounds which may be prepared in the described manner are the following:

1-methyl-3-( 3 '-methylaminopropyl)-2,1-

benzisothiazoline-2,2-dioxide, l-phenyl-3-(2'-methylaminoethyl)-2,1- benzisothiazoline-Z,2-dioxide, 1-ethyl-3 3 '-methylaminopropyl)-2, l

benzisothiazoline-Z,2-dioxide, l,3-dimethyl-3-( 3 '-'methylaminopropyl)-2, l

benzisothiazoline-2,2-dioxide, l-methyl-3-phenyl-3-(2'-ethylamino,ethyl)-2,l-

benzoisothiazoline-2,-2-dioxide, l-ethyl-3-methyl-3-( 3 '-methylaminopropyl)-2, l

benzisothiazoline-2,2-dioxide, l-methyl-3-( 3 '-aminopropyl)-2, l -benzisothiazoline- 2,2-dioxide, 1,3-dimethyl-3-( 3 '-aminopropyl )-2, l

benzisothiazoline-2,2-dioxide, l-ethyl-3-phenyl-3 3 -aminopropyl)-2,l-

benzisothiazoline-2,2-dioxide, 1-ethyl-3 methyl-3-( 2 '-aminoethyl)-2, l

benzisothiazoline-Z,2-dioxide. The compounds-in which Am is a cyclic amine group may be prepared by treating a l-substituted or 1,3-disubstituted-2,l-benzisothiazoline-2,2-dioxide with a suitable aminoalkyl ester such as an N-substituted heterocyclic halide or an N-substi-tuted heterocyclic alkyl halide in the presence ofa suitable base such as an alkali metal amide, in an inert reaction medium to .form the desired compound.

Representative of the esters which may be employed in the described manner are the following:

Nmethyl-3-chloropiperidine, N-ethyl-4-bromopiperidine, N-benzyl-3-chloropiperidine, N-benzyl-4-chloropiperidine, N-phenylpropyl-3-bromopiperidine,

' N-methyl-3-chlor0pyrrolidine, N-benzyl-3-bromopyrrolidine, N-isopropyl-4-brom opyrrolidine, N-phenylisopropyl-3-pyrrolidine, N-(beta-diethylaminoethyl )-3-chloropiperidine, N-(dimethylaminoethyl)-4-bromopiperidine, 3-chloroquinuclidine,

N-methyl-2-( 2-chloroethyl )piperidine, N-ethyl-3-chloromethylpiperidine, N-benzyl-4-(3-bromopropyl)piperidine, N-ethyl-2-( 2-chloroethyl)pyrrolidine, and N-benzyl-3-chloromethylpyrrolidine.

l-ethyl-3methyl-3-( 3 -pyrrolidyl)-2, l

benzisothiaioline-Z,2-dioxide, l ethyl:3 -phenyl-3-( 3 -pyrrolid'yl )-2, l

benzisothiazoline-Z,2-dioxide, l-methyl-3-[3'-(2"-pyrrolidyl)propyl] -2,lbenzisothiazoline-2, 2-dioxide, and

'l ,3-dimethyl-3-[2'-(4"-piperidyl)ethyl]- 2, l benzisothiazoline-2,2-diox ide. In addition to the previously described processes, the novel amines of the present invention may be prepared by other conventional techniques. For example, the

primary amines may be prepared by the hydrogenation of the corresponding nitriles which can in turn be Representative of the compounds which may be containing a secondary nitrogen in the ring can be produced by subjecting the corresponding compounds containing a benzyl group .on the nitrogen of the heterocyclic group to catalytic reductive cleavageto remove the benzyl group. Y

The catalytic reductive cleavage of the benzylgroup is readily effected by adding the appropriate N-benzyl piperidyl or pyrrolidyl derivative, advisably as an acid addition salt, to a solvent such as water or a lower alcoho'l,v adding a catalyst such as palladium and hydrogen under pressure, as up to about 100 psi. A small amount of glacial acetic acid is generally included to promote the reaction. The hydrogenation proceeds quickly and its progress can be measured by the hydrogen uptake, When the hydrogen uptake ceases prepared by treating the appropriate l-substituted or 1 ,B-disubstituted-Z, l -benzisothiazoline-2,2-dioxides with an afi-unsaturated nitrile such as acrylonitrile in the presencev of a suitable base such as potassium hydroxide. In addition to acrylonitrile, other a,B-un: saturated nitriles such as B-methyl-acrylonitrile may be T employed in the process.

The above process may be illustrated as follows:

CHzCHzCN Hi/Aatalyst in which allsymbols are as described and represent .groups which do not interfere with or partake in the reaction. v

the reaction can be considered completed. Afterfilter- 1 ing the reaction mixture it can be evaporated to dryness and the product tritura'ted with a solvent such as ether and separated by filtration.

Representative of the compounds which may be formed in this manner are the following:

l-methyl-3-(4'-piperidyl)-2, l -benzisothiazoline-2,2'-

dioxide, 1,3-dimethyl-3-(4'-piperidyl)-2,l-benzisothiazoline- 2,2-dioxide,

The primary amines in which B is larger than propylene may be preparedfror'n the nitriles obtained 'by treating the cyanoethyl derivative with alower altreating the tosylate with sodium cyanide to form the nitrile and repeating the whole process, if desired, to j add another methylene group. 1

This process may be illustrated as follows:

new.

in which all symbols represent groups which do not partake in or interfere with the reaction.

The primary amines may be used to prepare a wide variety of secondary and tertiary amines and amine derivatives by use of conventional techniques. For example, the secondary and tertiary amines which are not cyclic can be formed by simply treating the primary amine with a suitable organic halide. The primary amine can also be converted to the corresponding dialkyl substituted derivative by treating with a suitable acid and aldehyde, e.g., formic acid and formaldehyde. The secondary amines can be prepared by first treating the primary amine with benzaldehyde and then treating the product with hydrogen in the presence of Raney nickel to form the corresponding benzylamino tive.

The amines of the present invention may also be prepared by treating the'corresponding tosylate, the preparation of which has been previously described, with an appropriate amine.

deriva- Among the derivatives of the amines which can beprepared are the diacyl derivatives and the guanidino derivative. The diacyl derivative may be formed by treating the primary amine with an acid anhydride such as acetic anhydride. The guanidino derivative may be prepared by treating the primary amine with methyl pseudothiourea in 70 percent aqueous ethanol under reflux conditions.

The described processes may be illustrated as ,follows:

B-N(CO CH3): X

m S02 X N Y I v R wherein all symbols are as described and do not partake in or interfere with the reaction.

The compounds in which X and Y are other than hydrogen are preferably prepared by using conventional nitration, chlorination and the like techniques to place the ring substituent into the 1-substituted-2,lbenzisothiazoline-2,2-dioxide. For example, chlorine may be inserted into the 5 position by treating a l-substituted-2,l-benzisothiazoline-2,2-dioxide with N- ehlorosuccinimide in dimethylformamide.

Acid addition salts of the compounds of the present invention may be conveniently prepared by contacting the compounds with a suitable acid such as formic acid,

citric acid, maleic acid, sulfuric acid, hydrochloric acid, succinic acid, tartaric acid, benzoic acid'or fumaric acid.

Quaternary ammonium salts may be formed by contacting the compounds with a suitable alkylating agent such as dimethyl sulfate or an alkyl halide such as methyl chloride, methyl iodide or ethyl bromide.

The thiocyanic acid addition salts of the compounds when condensed with formaldehyde form resinous materials useful as pickling agents according to U.S. Pat. Nos. 2,425,320 and 2,606,155. The compounds also form fluosilicic acid addition salts which are useful as moth proofing agents according to U.S. Pat. Nos. 1,915,334 and 2,075,359.

The novel compounds of theinvention are pharmacologically active. For example, the compounds 1- methyl-3-dimethylaminoethyl-2, 1 -benzisothiaoline- 2,2-dioxide, l-methyl-3-benzylmethylaminoethyl-2,1- benzosothiazoline-2,2-dioxide, l-methyl-3-( 3 dimethylaminopropyl )-2 1 -benzisothiazoline-2, 2-di0xide, 1,3-dimethyl-3-( 3 '-aminopropyl)-2, 1 benzisothiazoline-2,2-dioxide, l,3-dimethyl-3-( 3 hydroxypropyl)-2,l -benzisothiazoline-2,2-dioxide, l ,3- dimethyl-3-(3'-morpholinopropyl)-2,lbenzisothiazoline-2,2-dioxide, l,3-dimethyl-3-( 3 aminopropyl)-5-chloro-2, l -benzisothiazoline, 1,3- dimethyl-3-( N-carbethoxy-2 '-aminoethyl)-2 l benzisothiazoline-2,2-dioxide and l,3-dime'thyl-3-(3- guanidinopropyl)-2,l-benzisothiazoline-2,2-dioxide, when evaluated in mouse behavioral studies at intraperitoneal doses of 3 to mg/kg of body weight were all found to produce behavioral profiles resembling those of known anti-hypertensive agents. In addition, the forementioned compounds were also found in doses up to 100 mg/kg to produce central nervous system stimulation as evidensed by an elevation of reactivity to stimuli, vocalization, pain response, pinnea hyperflexia and increased startle response. The mouse behavioral studies also indicated that the compounds were relatively safe and possessed LB values in excess of 100 mg/kg. The behavioral studies were conducted essentially in accordance with the procedure outlined by S. Irwin in Animal and Clinical Pharmacologic Techniques in Drug Evaluation, J. H. Nodine and P. E. Siegler, Ed. Year Book Medical Publishers, Inc. 1964. The forementioned compounds were also evaluated for hypertensive activity in the standard anesthetized, vagotomized dog preparation and found at intravenous doses of 1 0 mg/kg to decrease the blood pressure in the animals 10 to 25 percent or more. When intended for pharmaceutical use, the compounds are preferably combined with one or more suitable pharmaceutical diluents and formed into unit dosage forms such as tablets, capsules or solutions. Such dosage forms provide suitable means for oral and parenteral administration.

'The unit dosage forms may contain a concentration of 0.1 to percent or more by weight ofone or=more of the novel compounds. Generally, such dosage forms I will contain about 5 to 150mg. of the active in gredients. One or more of such dosage forms may be administered daily. I

The following examples are presented to illustrate this invention:

EXAMPLE 1 l-Methyl 3;-dimethylamir1oethyl-2,l-be nzisothiazoline- 2,2-d ioxide To a solution of 0.033 mole of potassium amide in 250 ml. of liquid ammonia is added in one portion 5.5 g. (0.03 mole) of l-methyl-2,l-benzoisothiazoline-2,2-

Y dioxide. The reaction mixture is stirred for 45 minutes and then treated dropwise with 5 equivalents of freshly distilled dimethylaminoethyl chloride, liberated from its HCl salt with solid KOH in a distillation apparatus on a steam bath. After-4 hours, stirring is discontinued and the ammonia allowedto evaporate. Water (100 ml.) and ether 150 ml.) were added to the residue, and

the separated aqueous layer extracted with two l00-ml. portions of ether- The ether solutions are combined and extracted with three l00-ml. portions of '10 percent solid NaOH, and washed three times with ether (100 ml.)-. Thecombined ether solution is dried (Na S0,) and evaporated. Elution 'of the residual oil from 250 g.- of alumina with benzene-ether l :1 yields 1 -methyl-3- dimethyl-aininoethyl-Z, l-benzisothiazoline-2,2dioxide in the form of a pale yellow oil. I I

' Anal. Calcd. for C,,'H,,N,O,S: C, 56.I66;'H',.7'.l3; S,

FoundzC, 56.22; H, 7.37; S, [2.76.

EXAMP E2 l -MethyI-B -benzylmethylaminoethyl-2, 1 -ben'- sizothiazoline-2,2-dioxide I The reaction of ll g. (0.06 mole) of the compound of Example l with 0.066 mole of potassium amide in 500 ml. of liquid ammonia for 20 minutes, followed by' the addition of 0.24 mole of I N-be'nzyl-N- methylaminoethyl chloride in 100 ml. of dry benzene gives, after a 6-hour reaction time and the work-up HCl, which likewise are combined, made alkaline with 250 ml. of ammonia for minutes and then with l5 g. (0.12 mole) of freshly distilled 3-dimethylaminopropyl chloride for 4'hours.'The usual isolation procedure affords a crude product which is eluted from 350 g. of

alumina with benzene-ether lzl as a nearly colorless Anal. Calcd. for C H N O S: C, 58.19; H, 7.51; S,

Found: C, 57.36; H, 7.84; S, 11.48.

EXAMPLE 4 1,3-Dimethyl-3-(3'-aminopropyl(-2,l-

1 benzisothiazoline-2,2-dioxide Hydrochloride A solution of 22 g. (0.088 mole) of l,3 dimethyl- 3 eluted from 150 g. of silica gel with chloroformmethanol (1:3) to give the amine as a light amber gum. Conversion of a portion of this material to the hydrochloride salt, followed by recrystallization from ethanol-ether, affords l,3-dimethyl-3-( 3 aminopropyl)-2', l-benzisothiazoline-2,2-dioxide proceduredescribed in Example 1,37 g. of an amber liquid. The excess aminoalkyl halide is distilled, and the residual oil put o n a column of 250 g. of alumina. Elution with benzene-ether (4:l provides l-methyl-3- benzylmethylaminoethyl-Z,l-benzisothiazoline-2,2- dioxide in'the form ofa yellow oil.

A portion of the amine is converted toa maleate salt,

which melts at 98-1-0l after recrystallizationfrom 2-' propanol-ether as a pale yellowpowder;

Anal. Calcd. for C,,H,,N,O,S: C, 59.17; H, 5.87; N,

Found: C, 59.27; H, 5,84; N, 6.l6.

' EXAMPLE 3 l-Methyl-3-(3.-dimethylaminopropyl)-2,l benzisothiazoline-2,2-dio ide The compound of Example l 5.5 g., 0.03 allowed to react with 0.033 mole of potassium amide in mole) is I hydrochloride in the form of an' off-white, nonhygroscopic powder, m.p. 173l75.

I Anal. Calcd. for C H ,ClN,O,S:C, 49.56; H, 6.58;- -Cl, 12.1918, 1 1.03.

Found: c, 49.74; H, 6.41; C1, 12.3s;'s', 11.20.

EXAMPLE 5 1 ,3-Dim'ethyl-3-(3 '-dimethylaminopropyl)-2, 1 benzisothiazoline-2,2-dioxide Hydrochloride A solution of 2.5 0.01 mole) of the amine of Example 4, 4 g. of percent'formic acid, and2 g. of 37 percent aqueous formaldehyde isheated on a steam bathfor 18 hours, then treated with 0.9 ml. of concentra ted hydrochloric acid, and concentrated under 1 vacuum. The residue is diluted with water (40 ml.), ex

tracted with ether, and made alkaline with solid sodium hydroxide. The separated oil is taken up in three SO-ml.

portions of ether, which are combined, dried 14.00,), and evaporated. Treatment of an ethereal solution of the residual oil with dry hydrogen chloride gives a gummy solid, which is recrystallizedfiometh anol- 'ether. The off-white granules of l,3-dimethy1 3-(3'- dimethylam inopropyl )-2, l -benzisothiazoline-2,2-dioxide hydrochloride melt at 177l 79. I I I Anal. Calcd. for c,,H,,c1N,o,s;c, 52.73; H, 7.27; N,8.78. i

Found: C, 52.63; H, 7.46; N, 8.94

I I EXAMP E 6 I l,3-Dim'ethyl-3-( N ,N-diacetyl-3 -aminopropyl )-2, l beriziso'thiazoline-Z,2-dioxide A A solution of the amine of Example4 (2.5 g., 0.01 mole) and 10 ml. of acetic anhydiide is heated on a steam-bath for 5 hours, t'he'ri poured into water and treated with solid sodium bicarbonate. The remaining ford a semi-solid. Recrystallization from chloroformpetroleum ether gives a solid, m.p. l16-130. This material is eluted from 40 g. of silica gel to give 1,3- dimethyl-3-( N,N-diacetyl-3 '-aminopropyl)-2, l benzisothiazoline-2,2-dioxide in the form of white granules, m.p. 133135 after recrystallization from chloroform-petroleum ether.

Anal. Calcd. for C H N O S: C, 56.78; H, 6.55; N, 8.28.

' Found: C, 56.66; H, 6.41; N, 8.11.

EXAMPLE 7 1,3-Dimethyl-3-(3 '-benzylaminopropyl)-2,1- benzisiothiazoline-2,2-dioxide A solution of the amine of Example 4 (4.4 g., 0.017 mole) and 1.8 g. (0.017 mole) of freshly distilled benzaldehyde in 75 ml. of dry benzene is refluxed in a water-separator apparatus for hours. The benzene is dried and evaporated, and the residual oil in ethanol reduced with hydrogen at 50 p.s.i. in the presence of Raney nickel. The catalyst is filtered, the filtrate evaporated, and the remaining oil eluted from 200 g. of alumina with benzene-ether (2:1). The product is isolated as an oil which slowly solidified during refrigeration under petroleum ether, m.p. 89.591.

Anal. Calcd. for C,,H, N,O,S: C, 66.24; H, 7.02; N, 8.13.

Found: C, 66.05; H, 7.21; N, 7.90.

EXAMPLE 8 1,3-Dimethyl-3-(3 '-guanidinopropyl)-2, 1 benzisothiazoline-2,2-dioxide Sulfate A solutionof the amine of Example 4 (2.54g., 0.01 mole) and 1.4 g. (0.005 mole) of methyl pseudothiourea in 40 ml. of 70 percent aqueous ethanol is refluxed for 15 hours and then evaporated to dryness. The

residual gum eventually solidifies after being forced out of methanol with 2-propanol, followed by refrigeration under dry ether. The 1,3-dimethyl-3-(3- guanidinopropyl )-2, l -be'nzisothiazoline -2,2-dioxide sulfate in the form of a white powder melts at l20-135 as a foam.

Anal.Ca1cd..for c,,H,,N,o,s,; c, 45.20; H, 6.1 3.

Found: c, 45.27;11, 6.50.

I 7 EXAMPLE 9 1,3-Dimethyl-3-(3 -methylbenzylaminopropyl )-2, l

benzylaminoproply)-2,1-benzisothiazoline-2,2-dioxide hydrochloride in the form of a colorless oil. The hydrochloride salt prepared from it melts at 202-203 after recrystallization from ethanol-ether.

Anal. Calcd. rorc n mmsnclz S'HCl. 60.81; H, 6.89; N, 7.09.

Found: C, 60.90; H, 6.93; N, 7.18.

EXAMPLE l0 1,3 Dimethyl-3-(N-carbethoxy-2-aminoethyl)-2,lbenzisothiazoline-2,2-dioxide To a solution of sodium (2.3 g., 0.10 g.-atom) in 150 ml. of ethanol under nitrogen is added 13.4 g. (0.05 mole) ofthe 1,3-dimethyl-3-(2'-carbamylethyl)-2;1- benzisothiazole-2,2-dioxide, and the resulting mixture is cooled and treated dropwise with 8 g. (0.05 mole) of bromine in 50 ml. of ethanol. The milky solution is allowed to warm to room temperature, refluxed for 3 hours, acidified with acetic acid, and partially evaporated under vacuum. The remaining liquid is diluted with water (500 ml.) and extracted with two -ml. portions of ether, which are combined, extracted twice with saturated NaHCO solution, washed with saturated brine, dried (K,CO,Na,So and evaporated. Elution of this material from alumina with ether-chloroform 1:4) gives 1,3-dimethyl-3-(N-carbethoxy-2 '-aminoethyl)-2,1-benzisothiazoline-2,2- dioxide in the form of a pale yellow oil.

Anal. Calcd. for C, H, N,O,S: C, 53.85; H, 6.45; N, 8.97; S, 10.27.

Found: C, 53.77; H, 6.45; N, 9.01; S, 9.99.

- EXAMPLE 1 l.

. mixture is stirred for l hour at room temperature and then treated with water. The ether layer is separated, dried Na,SO and evapor'atedElution of the residual pale yellow oil from 240 g. ofsilicagel' with etherchloroform (4:1) affords 1,3-dimethyl-3-(3'-hydroxypropyl)-2,1-benzisothiazoline-2,2-dioxide in the form of a colorless oil.

Anal. Calcd. for C,,H, NO,S: C, 56.44; H, 6.71; N,

Found: C, 55.92; H, 6.81; N, 5.16; S, 12.34.

EXAMPLE 12 1,3-Dimethyl-3-(3 '-hydroxypropyl)-2, 1 benzisothiazoline-2,2-dioxide Tosylate To a solutionof the carbinol of Example 1 l (l0.7 g.,

0.042 mole) in 60 ml. of dry benzene under nitrogen is added 2 g. (0.045 mole) of 53 percentsodium hydride dispersion The mixture is stirred at 25 for 1 hour, refluxed for 1 hour, cooled, and treated with a solution of 8 g. (0.042 mole) of tosyl chloride in 50 ml. of benzene. The reaction mixture is refluxed for 8' hours, then stirred at room temperature for an additional 10 hours. Water is added, and the organic layer separated,

. dried (Na,SO,), and evaporated. The residual oil is eluted from 300 g. of silica gel. Benzene-ether (3:1 affords the tosylate as an oil. Refrigeration of the tosylate under petroleum ether yields l,3-dimethyl-3-(3- hydroxypropyl)-2,lbenzisothiazoline-2,2-dioxide tosylate in the form ofa white, powdery solid, mp. 8890.

Anal. Calcd. for C,,,H ,,NO,SI C, 55.72; H, 5.66; N,

Found: C, 56.14; N, 5.55; N, 3.34.

EXAMPLE 13 l,3-Dimethyl-3-( 3 '-morpholinopropyl)-2,lbenzisothiazoline-2,2 dioxide Hydrochloride v A solution of the tosylate of Example 12 (4.1 g., 0.01 mole), as an oil, and 1.92 (0.022 mole) of morpholine in 50 ml. of dry toluene is refluxed for 20 hours, cooled, and poured into a mixture of benzene (40 ml.) percent aqueous NaOH (40 ml.). The organic phase is washed several times with water, dried, and evaporated. The residual oil is treated with ethereal HCl to afford a light tan powder, which is recrystallized from ethanol-methanol-ether to give the l',3-dimethyl- 3-( 3 -morpholinopropyl)-2,1-benzisothiazoline-2,2- dioxide hydrochloride, m.p. 202-203.

Anal. Calcd. for C,,,H ,,ClN O S: C, 53.24; H, 6.98; N, 7.76. 1

Found: C, 53.55; H, 7.08; N, 7.87.

We claim: 1. A compound selected from the class consisting of compounds of the formula Rr B-Am X X & I S p X l R in which X and Y are hydrogen, lower alkyl of one to four carbon atoms, nitro, lower alkoxy of one to three carbon atoms, halogen or CF,,; R is an alkyl of oneto four carbon atoms, a cycloalkyl of three to seven carbon atoms, a cycloalkyl-lower alkyl in which the cycloalkyl contains three to seven carbon atoms and the lower alkyl contains one to four carbon atoms,

3. A compound of claim 1 in which R and R are lower alkyl of one to four carbon atoms.

4. A compound of claim 1 in which X and Y are hydrogen,,R and R, are methyl, B is propylene and A is 5. A compound of claim 1 in which X and Y are hydrogen, R and R, are methyl, B is ethylene and Am is in which R, is carbethoxy and R, is hydrogen.

. 6. A compound of claim 1 in which X and Y are hydrogen, R and R, are methyl, B is propylene and Am is hydroxy.

7. A compound of claim 1 in which X and Y are hydrogen, R and R, are methyl, B is propylene and Am is in which R and R are acetyl. 

2. A compound of claim 1 in which X and Y are selected from hydrogen, alkyl of one to four carbon atoms, nitro, hydroxy, alkoxy of one to three carbon atoms, halogen or CF3, and Am is
 3. A compound of claim 1 in which R and R1 are lower alkyl of one to four carbon atoms.
 4. A compound of claim 1 in which X and Y are hydrogen, R and R1 are methyl, B is propylene and Am is
 5. A compound of claim 1 in which X and Y are hydrogen, R and R1 are methyl, B is ethylene and Am is
 6. A compound of claim 1 in which X and Y are hydrogen, R and R1 are methyl, B is propylene and Am is hydroxy.
 7. A compound of claim 1 in which X and Y are hydrogen, R and R1 are methyl, B is propylene and Am is 